One of the major issues involving treatment involves the toxicity and/or adverse effects of pharmaceuticals that complicate the treatment of various conditions. Systemically administered medications tend to have effects that are undesirable when the therapeutic objective of the treatment is considered. If a pathology affects only a particular part or organ in the body, it is desirable to only administer treatment to that particular part or organ. In the prior art it has been known to provide localized radiation treatment by implanting radioactive pharmaceuticals in an organ that is to be treated so that radiation will be substantially confined to that organ. Most other implants have been intended to provide a systemic effect.
Two sustained delivery systems in the form of ophthalmic inserts that have been developed for commercial use are the Ocusert system (Akorn) and Lacrisert® (Aton). The Ocusert device is designed to provide for the release of medication at predetermined and predictable rates, which permits the elimination of frequent dosing by the patient, ensures nighttime medication, and provides a better means of patient compliance. The insert is elliptical with dimensions of 13.4 by 4.7 mm and 0.3 mm in thickness. The insert is flexible and is a multilayered structure consisting of a drug-containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate. The rate of drug diffusion is controlled by the polymer composition, the membrane thickness, and the solubility of the drug. The devices are sterile and do not contain preservatives. Ocusert inserts containing pilocarpine have been used in glaucoma therapy. After placement in the conjunctival fornix, the inserts are designed to release medication at the desired rates over a 7-day period at which time they are removed and replaced with new ones.
The Lacrisert® insert is a sterile, translucent, rod-shaped, water-soluble form of hydroxypropyl cellulose. The product is inserted into the inferior cul-de-sac of the eye of patients with dry eye states. The insert acts to stabilize and thicken the precorneal tear film and to delay its breakup. Inserts are typically placed in the eye once or twice daily. Following administration, the inserts soften and slowly dissolve.
The following U.S. patents disclose various ocular inserts for medicinal therapy. U.S. Pat. No. 4,730,013 to J. V. Bondi, et al., assigned to Merck & Company, Inc., discloses ocular inserts with or without pharmaceutically active agents, comprising 75% to 100% of a matrix of 15% polyvinyl alcohol, 10% glycerine, 75% hydroxy propyl methylcellulose phthalate, and 0-25% of a pharmacologically active agent. U.S. Pat. No. 5,637,085 describes the making of an implantable wafer for the treatment of solid cancer tumors.
U.S. Pat. No. 4,522,829 to Andreas Fuchs, et al., (Merck GmbH), discloses an intraocular pressure-lowering film insert of a 1-(p-2-iso-propoxyethoxy methyl-phenoxy)-3-isopropylamino-propan-2-ol or a physiologically acceptable salt thereof and an ophthalmically acceptable carrier.
U.S. Pat. No. 4,432,964 to Robert M. Gale (Alza Corp.) discloses an ocular insert for treating inflammation made of a pair of micronized steroids consisting of two topically acceptable different chemical therapeutic forms of betamethasone or a derivative, and a bio-erodible polymeric polyorthoester carrier.
U.S. Pat. No. 4,346,709 to Edward E. Schmitt (Alza Corp.) discloses an erodible device for delivering a drug to an environment of use, which includes a poly(orthoester) or a poly(orthocarbonate).
U.S. Pat. No. 4,303,637 to Robert M. Gale, et al., discloses an ocular insert composed of a beta
U.S. Pat. No. 4,303,637 to Robert M. Gale, et al., discloses an ocular insert composed of a beta blocking drug in a polymer with the drug surrounded by the polymer selected from the group consisting of poly(olefin), poly(vinylolefin), poly(haloolefin), poly(styrene), poly(vinyl), poly(acrylate), poly(methacrylate), poly(oxide), poly(ester), poly(amide), and poly(carbonate).
U.S. Pat. No. 4,190,642 (Alza Corp.) discloses an ocular insert composed of a discrete depot of a pilocarpine solute and an epinephrine solute, a film of an ethylene-vinyl ester copolymer forming the insert, where fluid from the environment is imbibed through the wall into the depots to continually dissolve the solutes and release the formulation.
U.S. Pat. No. 4,093,709 to Nam S. Choi (Alza Corp.) discloses an ocular insert composed of an orthoester and an orthocarbonate polymer.
U.S. Pat. No. 3,993,071, issued Nov. 23, 1976 to Takeru Higuchi, et al., discloses a bio-erodible ocular insert for the controlled administration of a drug to the eye from 8 hours to 30 days, in which the drug formulation can also be microencapsulated and the microcapsules dispersed in the drug release rate controlling material.
U.S. Pat. No. 3,981,303 to Takeru Higuchi, et al. (Alza Corp.) discloses an ocular insert for the continuous controlled administration of a drug to the eye composed of a plurality of microcapsule reservoirs comprised of a drug formulation confined within a drug release rate controlling material, distributed throughout a bio-erodible matrix permeable to the passage of the drug at a higher rate than the rate of drug passage through the drug release rate controlling material, where the device is of an initial shape and size that is adapted for insertion and retention in the sac of the eye. The hydrophobic material may be selected from cholesterol, waxes, C.sub.10 to C.sub.20 fatty acids, and polyesters, and the drug may be selected from epinephrine, pilocarpine, hydrocortisone, idoxuridine, tetracycline, polymixin, gentamycin, neomycin, and dexamethasone.
U.S. Pat. No. 3,960,150 to Takeru Higuchi, et al. (Alza Corp.) discloses an ocular insert for the continuous controlled administration of a drug to the eye composed of a body of hydrophobic bio-erodible drug release rate controlling material containing a drug, where the body is of an initial shape adapted for insertion in the sac of the eye, where the drug release rate controlling material can be a polyester, and the drug may be selected from epinephrine, pilocarpine, hydrocortisone, idoxuridine, tetracycline, polymixin,
U.S. Pat. No. 3,811,444, issued May 21, 1974 to Richard W. Baker, et al., assigned to the Alza Corp., discloses an ocular insert for the continuous controlled administration of a drug to the eye comprising a drug formulation dispersed through a body of selected hydrophobic polycarboxylic acid which erodes over time to dispense the desired amount of drug. The polycarboxylic acid can be a copolymer of an acid from the group of maleic acid, acrylic acid, lower alkyl acrylic acids from about 4 to about 6 carbon atoms, with a copolymerizable olefinically unsaturated material selected from the group consisting of ethylene, propylene, butadiene, isoprene and styrene and the lower alkyl vinyl ethers.
U.S. Pat. No. 3,630,200, issued Dec. 28, 1971, to Takeru Higuchi, assigned to the Alza Corporation, discloses a drug-dispensing ocular insert for insertion into the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lid where the inner core contains the drug and is surrounded by a soft hydrophilic outer layer, where the outer layer can be composed of a polymer selected from the group consisting of hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate and cellulosic gel. The inner core may be a polymer selected from the group of plasticized or unplasticized polyvinylchloride, plasticized nylon, unplasticized soft nylon, silicone rubber, polyethylene, hydrophilic hydrogel of an ester of acrylic or methacrylic acid, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl alcohol, cross-linked partially-hydrolyzed polyvinylacetate, cellulosic gel, ion-exchange resin and plasticized polyethylene terephthalate.
U.S. Pat. No. 3,618,604 to Richard A. Mess (Alza Corporation) discloses a drug-dispensing ocular insert adapted for insertion into the cul-de-sac of the eye, where the insert is a tablet containing a reservoir of drug formulation within a flexible polymeric material, and the polymeric material is formed of plasticized or unplasticized polyvinylchloride, plasticized nylon, unplasticized soft nylon, plasticized polyethylene terephthalate, silicon rubber, hydrophilic hydrogel of a ester of acrylic or methacrylic acid, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl alcohol, and cross-linked partially-hydrolyzed polyvinylacetate.
U.S. Pat. Nos. 3,993,071; 3,986,510; 3,981,303, 3,960,150, and 3,995,635 to Higuchi, et al., disclose a biodegradable ocular insert made from zinc alginate, poly(lactic acid), poly(vinyl alcohol), poly(anhydrides), and poly(glycolic acid).
A number of patents disclose the use of drug-loaded polyanhydrides (wherein the anhydride is in the backbone of the polymer) as matrix materials for ocular inserts. See, in general, U.S. Pat. Nos. 5,270,419; 5,240,963; and 5,137,728. Other U.S. patents that describe the use of polyanhydrides for controlled delivery of substances include: U.S. Pat. No. 4,857,311 to Domb and Langer, entitled “Polyanhydrides with Improved Hydrolytic Degradation Properties,” which describes polyanhydrides with a uniform distribution of aliphatic and aromatic residues in the chain, prepared by polymerizing a dicarboxylic acid with an aromatic end and an aliphatic end); U.S. Pat. No. 4,888,176 to Langer, Domb, Laurencin, and Mathiowitz, entitled “Controlled Drug Delivery High Molecular Weight Polyanhydrides,” which describes the preparation of high molecular weight polyanhydrides in combination with bioactive compounds for use in controlled delivery devices); and U.S. Pat. No. 4,789,724 to Domb and Langer, entitled “Preparation of Anhydride Copolymers,” which describes the preparation of very pure anhydride copolymers of aromatic and aliphatic diacids.
U.S. Pat. No. 5,075,104 discloses an ophthalmic carboxyvinyl polymer gel for the treatment of dry eye syndrome.
U.S. Pat. No. 4,407,792 discloses an aqueous gel that includes a gel-forming amount of an ethylene-maleic anhydride polymer.
U.S. Pat. No. 4,248,855 discloses the salt of pilocarpine with a polymer containing acid groups for use as an ocular insert, among other things.
U.S. Pat. No. 4,180,064 and U.S. Pat. No. 4,014,987 disclose the use of poly(carboxylic acids) or their partially esterified derivatives as drug delivery devices. PCT/US90/07652 discloses that biologically active compounds containing a carboxylic acid group can be delivered in the form of an anhydride of a carrier molecule that modifies the properties of the molecule. U.S. Pat. No. 5,322,691 discloses the use of pressure to form drug containing ocular inserts from polymers with pressures up to 12 tons. The insets are made by mixing the drug powder with a polymer prior to compressing the mixture. There is no mention of the application of pressure to microspheres and polymers to form a dispensing device.
Although these patents disclose a number of types of ocular inserts, there is still a need to provide new dosage forms with modified properties for the delivery of local delivery of therapeutic agents. In particular, there is a need to provide a dispensing device that provides for the long acting local delivery of therapeutic agents to the eye and other locations in the body.
The formulations comprise a matrix of a polymer carrier and an active drug where the matrix is made by compression of micro or nano particles of a therapeutic agent in combination with a polymer. The matrix is positioned in or near the location where it will make available the therapeutic agent for treating or preventing pathologic conditions. The preferred polymeric matrix combines the characteristics of stability, strength, flexibility, low melting point, dispersability and suitable degradation profile. The matrix must retain its integrity for a suitable time so that it may be handled and placed in an aqueous environment, such as the eye, pancreas, liver, adrenal gland, colon, without loss of structural integrity. It should also be stable enough to be stored and shipped without loss of structural integrity. The matrix is designed to disintegrate into its constituent particles shortly after it is placed in position to release the therapeutic agent. Gliadel Implant Wafer (Eisai Corp. of N. Amer.) made of carmustine in polifeprosan intracranial implant wafer, is a white, dime-sized wafer made up of a biocompatible polymer that contains the cancer chemotherapeutic drug, carmustine (BCNU). After a neurosurgeon removes a high-grade malignant glioma, up to eight wafers can be implanted in the cavity where the tumor resided. Once implanted, Gliadel slowly dissolves, releasing high concentrations of BCNU into the tumor site. The specificity of Gliadel minimizes drug exposure to other areas of the body. Other recent products based on drug-loaded biodegradeable microspheres have reached the pharmaceutical marketplace. Drugs such as Lupron Depot (Abbott Laboratories), Trelstar Depot (Watson Pharmaceuticals) and Risperdal Consta (Ortho-McNeil-Janssen Pharmaceuticals) offer injectable parenteral drug delivery in depot formulations (IM or SC). Targeted local therapy include Bausch & Lomb's Retisert® a sterile nonbiodegradable implant that continuously delivers fluocinolone acetonide to the posterior segment of the eye.
U.S. Pat. No. 5,019,400 discloses a process for preparing microspheres using very cold temperatures to freeze polymer-biologically active agent mixtures into polymeric microspheres with very high retention of biological activity and material.
U.S. Pat. No. 6,183,781 discloses a process for fabricating implantable wafers produced by compression of: (1) polymer matrix fragments containing cryogenically pre-dispersed protein crystal produced by mechanical grinding, or (2) microcapsules produced by cryogenically suspending protein crystals in polymer solutions and coating them with a layer of polymer. The practical result of producing [polymer/protein crystal] fragments by mechanically grinding a cryogenically casted polymer-protein crystal slab is the formation of a highly heterogeneous mixture of polymer fragments, fractured protein crystal and protein crystal (full or partial) entrapped in polymer fragments. The microcapsule formation method described is a process to encapsulate either individual protein crystal or a cluster of protein crystals, which is analogous to coating protein crystals with a layer of polymer, followed by compression. In both cases, drug was not co-dissolved in the polymer solution to formulate microspheres or nanospheres with drugs uniformly dispersed/distributed inside the nano or microsphere matrices.
U.S. Pat. No. 7,462,366 discloses a process for preparing a drug delivery particle including a reservoir region having primarily large pores and a metering region. The particle can be highly spherical.
There remains a significant unmet need for dispensing devices that provide for the local delivery of long acting formulations of therapeutic agents. The applicants have devised formulations which comprise a matrix of a polymer carrier and an active drug where the matrix is made by hyper-compression of micro or nano particles of a therapeutic agent in combination with a polymer via modified high compression machines and/or dies. The matrix is positioned in the body in a location where it will be available for absorption to produce a substantially local effect. The preferred polymeric matrix combines the characteristics of stability, strength, flexibility, low melting point, dispersability and suitable degradation profile. The matrix must retain its integrity for a suitable time so that it may be handled and placed in an aqueous environment without loss of structural integrity. It should also be stable enough to be stored and shipped without loss of structural integrity. The matrix is designed to disintegrate into its constituent particles shortly after it is placed in position to release the therapeutic agent to the area where it will be available for therapeutic purposes.